PMID- 28981117 OWN - NLM STAT- MEDLINE DCOM- 20180608 LR - 20220410 IS - 2041-4889 (Electronic) VI - 8 IP - 10 DP - 2017 Oct 5 TI - Trehalose ameliorates oxidative stress-mediated mitochondrial dysfunction and ER stress via selective autophagy stimulation and autophagic flux restoration in osteoarthritis development. PG - e3081 LID - 10.1038/cddis.2017.453 [doi] AB - Oxidative stress-related apoptosis and autophagy play crucial roles in the development of osteoarthritis (OA), a progressive cartilage degenerative disease with multifactorial etiologies. Here, we determined autophagic flux changes and apoptosis in human OA and tert-Butyl hydroperoxide (TBHP)-treated chondrocytes. In addition, we explored the potential protective effects of trehalose, a novel Mammalian Target of Rapamycin (mTOR)-independent autophagic inducer, in TBHP-treated mouse chondrocytes and a destabilized medial meniscus (DMM) mouse OA model. We found aberrant p62 accumulation and increased apoptosis in human OA cartilage and chondrocytes. Consistently, p62 and cleaved caspase-3 levels increased in mouse chondrocytes under oxidative stress. Furthermore, trehalose restored oxidative stress-induced autophagic flux disruption and targeted autophagy selectively by activating BCL2 interacting protein 3 (BNIP3) and Phosphoglycerate mutase family member 5 (PGAM5). Trehalose could ameliorate oxidative stress-mediated mitochondrial membrane potential collapse, ATP level decrease, dynamin-related protein 1 (drp-1) translocation into the mitochondria, and the upregulation of proteins involved in mitochondria and endoplasmic reticulum (ER) stress-related apoptosis pathway. In addition, trehalose suppressed the cleavage of caspase 3 and poly(ADP-ribose) polymerase (PARP) and prevented DNA damage under oxidative stress. However, the anti-apoptotic effects of trehalose in TBHP-treated chondrocytes were partially abolished by autophagic flux inhibitor chloroquine and BNIP3- siRNA. The protective effect of trehalose was also found in mouse OA model. Taken together, these results indicate that trehalose has anti-apoptotic effects through the suppression of oxidative stress-induced mitochondrial injury and ER stress which is dependent on the promotion of autophagic flux and the induction of selective autophagy. Thus, trehalose is a promising therapeutic agent for OA. FAU - Tang, Qian AU - Tang Q AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Zheng, Gang AU - Zheng G AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Feng, Zhenhua AU - Feng Z AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Chen, Yu AU - Chen Y AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Lou, Yiting AU - Lou Y AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Wang, Chenggui AU - Wang C AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Zhang, Xiaolei AU - Zhang X AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Zhang, Yu AU - Zhang Y AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Xu, Huazi AU - Xu H AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Shang, Ping AU - Shang P AD - Department of Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. FAU - Liu, Haixiao AU - Liu H AUID- ORCID: 0000-0003-0994-2005 AD - Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi Road, Wenzhou 325027, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171005 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (BNip3 protein, mouse) RN - 0 (Membrane Proteins) RN - 0 (Mitochondrial Proteins) RN - 0 (P62 protein, human) RN - 0 (RNA, Small Interfering) RN - 0 (RNA-Binding Proteins) RN - 955VYL842B (tert-Butylhydroperoxide) RN - B8WCK70T7I (Trehalose) RN - EC 3.1.3.16 (PGAM5 protein, human) RN - EC 3.1.3.16 (Phosphoprotein Phosphatases) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Autophagy/drug effects/*genetics MH - Chondrocytes/drug effects/metabolism MH - DNA Damage/drug effects MH - Endoplasmic Reticulum Stress/drug effects/genetics MH - Humans MH - Membrane Proteins/genetics MH - Mice MH - Mitochondrial Proteins/genetics MH - Osteoarthritis/drug therapy/*genetics/pathology MH - Oxidative Stress/drug effects/*genetics MH - Phosphoprotein Phosphatases/genetics MH - RNA, Small Interfering/administration & dosage MH - RNA-Binding Proteins/genetics MH - Trehalose/administration & dosage/*genetics MH - tert-Butylhydroperoxide/toxicity PMC - PMC5680575 COIS- The authors declare no conflict of interest. EDAT- 2017/10/06 06:00 MHDA- 2018/06/09 06:00 PMCR- 2017/10/01 CRDT- 2017/10/06 06:00 PHST- 2017/05/25 00:00 [received] PHST- 2017/08/06 00:00 [revised] PHST- 2017/08/09 00:00 [accepted] PHST- 2017/10/06 06:00 [entrez] PHST- 2017/10/06 06:00 [pubmed] PHST- 2018/06/09 06:00 [medline] PHST- 2017/10/01 00:00 [pmc-release] AID - cddis2017453 [pii] AID - 10.1038/cddis.2017.453 [doi] PST - epublish SO - Cell Death Dis. 2017 Oct 5;8(10):e3081. doi: 10.1038/cddis.2017.453.